Method and apparatus for the stimulation of hair growth

ABSTRACT

A method for activating or inhibiting the differentiation of stem cells including exposing the stem cells to a source of narrowband multi chromatic electromagnetic radiation under conditions effective to activate or inhibit cell differentiation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/212,916, filed Aug. 29, 2005, which is a continuation of U.S.application Ser. No. 09/986,367, now U.S. Pat. No. 6,936,044, filed Nov.8, 2001, which is a continuation-in-part of U.S. application Ser. No.09/819,081, now U.S. Pat. No. 6,629,971, filed Feb. 15, 2001, which is adivisional application of U.S. application Ser. No. 09/203,178, now U.S.Pat. No. 6,238,956, filed Nov. 30, 1998, which are all herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention generally relates to a system and method for thestimulation of hair growth, using a novel combination of photothermal,photochemical and photomodulatory alone or by also applying a drug or acosmeceutical composition, naturally occurring chromophore, or otherlight-activated chromophore to or into the hair follicle hair bulb, hairbulge, hair stem cell or surrounding tissue and exposing the compositionto electromagnetic radiation.

BACKGROUND OF THE INVENTION

There are several known techniques for attempting to reduce or eliminatehair growth in human skin. A few of these known techniques such astopical minoxidil or the commercially available product “Rogaine” arescientifically proven and widely accepted as effective. However, theirdegree of efficacy varies greatly.

There are several processes which may be used for producing preferentialdamage of the hair but relatively few are known which stimulate hairgrowth. In one process the target may be natural melanin pigment in thehair shaft and surrounding supporting tissues. In another process thetarget may be an external chromophore or contaminant. Most of theseprocesses tend to damage the hair, either by producing heat or byphoto-acoustical shock waves. These known processes have varying degreesof effectiveness, but require multiple treatments and, in their currentform, produce only partial permanent hair reduction.

In recent years the use of light sources to reduce or eliminate unwantedhair growth has been developed. One known technique selects a wavelengthof laser light that is well-absorbed by the naturally occurring “native”pigments in the hair shaft (and perhaps some pigment in parts of thehair duct or hair follicle cells).

Another known technique uses a short pulsed laser to produce awavelength that may be absorbed by a “foreign” material or “skincontaminant”. Aspects of this technique are described, for example, inU.S. Pat. Nos. 5,423,803; 5,817,089; 5,425,728; 5,226,907, and5,752,949, all of which are incorporated by reference. This contaminantmay be applied directly onto the skin and may be introduced into theempty space surrounding the hair shaft. One contaminant that has beenused is carbon graphite in particulate form. The graphite particles havea diameter that is small enough to enable the particles to drop from thesurface of the skin into the free empty spaces between the duct and thehair shaft. The energy from a laser may then interact with thecontaminant particles. This causes injury to surrounding tissues whosefunction is to support the growth of the hair shaft. This tends toreduce or eliminate hair growth.

These contaminant particles are not physically incorporated into thehair shaft or into the surrounding hair follicle, hair bulge or hairduct cells. Nor do these contaminant particles chemically,immunologically, biologically or otherwise interact, react or complexwith the hair shafts or tissue cells. The contaminant particles simplyphysically occupy the space surrounding the hair shaft. Another knownhair removal technique is to use a pulsed electromagnetic radiationsource to produce a wavelength that may be absorbed by hair, asdescribed, for example, in U.S. Pat. No. 5,683,380, which isincorporated by reference.

There are problems with present light and laser hair removal techniques.Known melanin targeting systems work reasonably well and are reasonablysafe only when the color of the hair is very dark and when the skin isvery light and not tanned. Virtually all light sources which tend totarget melanin are also inherently absorbed by the overlying andsurrounding skin. At present, these light sources cannot be safely usedat optimal very high power settings for people with darker skin or evenpeople with a dark tan.

Dying the hair allows increased damage to the hair target, helps confinedamage to the hair target, and enables the use of power settings thatare not so high as to damage surrounding and overlying skin. Treatmentswhich target melanin inherently do not work well on light hair, sincethere is not enough natural pigment to absorb enough energy to damagehair even if the power is quite high. Using hair dye enables thisobstacle to be overcome.

A known hair removal process which uses a 1064 nm laser to produce awavelength that may be absorbed by a skin contaminant appears to be safeon all skin colors, including darker skin colors. However, this safetyis a consequence of there being very little melanin absorption. It istherefore necessary to add graphite particles in oil contaminant lotionbefore laser treatment. This graphite particle lotion does not enterinto the hair shaft itself. Instead, the graphite lotion tends to occupyempty spaces surrounding the hair shaft as it sits in the hair duct.This presents a problem. Either an insufficient or sub-optimal number ofgraphite particles penetrate into the hair duct, or an insufficientamount of damage is caused by the graphite particles. Consequently, manytreatments tend to be required before an acceptable result is achieved.

SUMMARY OF THE INVENTION

The present invention relates to a method for stimulating hair growth inwhich the a hair growth structure is exposed to a source ofelectromagnetic radiation having a dominant emissive wavelength of fromabout 390 nm to about 1600 nm. By way of definition, the dominantemmisive wavelength is the primary wavelength emitted by the source ofelectromagnetic radiation, i.e., that wavelength is emitted at a greaterintensity than any other wavelength. Photostimulating the hair growthstructure is then performed by maintaining the exposure of the hairgrowth structure to the source of electromagnetic radiation for aclinically effective duration and at a clinically effective lightintensity. Clinically effective durations and intensities are furtherdescribed in the detailed description of the invention and examples andcan include single pulses from a single source of electromagneticradiation, multiple pulses from a single source of electromagneticradiation, multiple pulses from multiple sources of electromagneticradiation, single pulses from multiple sources of electromagneticradiation, simultaneous pulses from multiple sources of radiation, andcombinations thereof.

The exposure to electromagnetic radiation may be enhanced by way of theuse of penetration enhancing agents or photomodulating agents. Exemplaryof such agents, whose function is to enhance are selected from the groupconsisting of at least one of Vitamin C, Vitamin E, Vitamin A, VitaminK, Vitamin F, Retin A (Tretinoin), Adapalene, Retinol, Hydroquinone,Kojic acid, a growth factor, Echinacea, an antibiotic, an antifungal, anantiviral, a bleaching agent, an alpha hydroxy acid, a beta hydroxyacid, salicylic acid, antioxidant triad compound, a seaweed derivative,a salt water derivative, an antioxidant, a phytoanthocyanin,epigallocatechin-3-gallate, a phytonutrient, a botanical product, aherbaceous product, a hormone, an enzyme, a mineral, a geneticallyengineered substance, a cofactor, a catalyst, an anti aging substance,insulin, trace elements (including ionic calcium, magnesium, etc),minerals, minoxidil, a hair growth stimulating substance, a hair growthinhibiting substance, a dye, a natural or synthetic melanin, ametalloproteinase inhibitor an inhibitor of AP-1 or c-Jun, proline,hydroxyproline, an anesthetic substance, chlorophyll, copperchlorophyllin, chloroplasts, carotenoids, bacteriochlorophyll,phycobilins, carotene, xanthophyll, anthocyanin, and derivatives,subcomponents, and analogs of the above, both natural and synthetic, andmixtures thereof. The list is meant to be illustrative and notexhaustive, as those of ordinary skill in the art will recognize, basedon the disclosure herein, that other compounds are capable of treatingthe upper layers of the skin, hair structures, and surrounding tissue toenhance treatment with electromagnetic radiation.

Further, physical procedures may be performed to permit greaterpenetration of electromagnetic radiation into target hair structure,skin, and surrounding tissue in preparation for treatment. Suchprocedures include, but are not limited to: enzyme peel, microdermabrasion, solvent stripping, tape stripping, scrubbing, laser ablation,laser vaporization, chemical peeling, electrical stimulation, lasertreatments using high peak power and short pulse durations, ultrasound,or combinations thereof.

Finally, the source or sources of electromagnetic radiation for use withthe present invention are essentially unlimited. The criteria forselection of the source is treatment dependent and is only limited toemitters of electromagnetic radiation in the range of from about 300 nmto about 1600 nm, either directly or after mechanical or electricalfiltration of the radiation. Most preferred among such emitters, due totheir cost and availability are light emitting diodes (LED's), lasers,flashlamps, fluorescent lights, dye lasers, diode lasers, andincandescent sources filtered to produce a dominant emissive wavelengthin the desired range.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematical illustration of various treatment regimens,including the low level light method of the present invention which mayalso incorporate the use of topical formulations.

FIG. 2 is a schematical representation of treatment regimens pertainingto the use of low level light according to the present invention.

FIG. 3 is an illustration of an embodiment of an LED array of thepresent invention having multiple panels of arrays.

FIG. 4 is a graphical illustration of the absorption spectrum of humanfibroblast overlayed with the wavelengths used by narrowband, multichromatic LED emitters of the present invention and also the absorptionspectrum of indocyanine green (ICG).

FIG. 5 is a graphical illustration of the absorption spectrum of humanfibroblast overlayed with the wavelengths used by narrowband,multichromatic LED emitters of the present invention and also theabsorption spectrum of protophorphyrin IX, one of the activechromophores in acne bacteria.

FIG. 6 is a graphical illustration of the absorption spectrum of humanfibroblast overlayed with the wavelengths used by laser emitters.

FIG. 7 illustrates in perspective the spacing of the optoelectronicdevices of the present invention in close packed spacing in onedimension.

FIG. 8 show an array of optoelectronic devices arranged into threepanels. The cross hatched areas represent protective covers. The coversmay transmit light or may diffuse light. The set of three panels shownare hinged to allow adjustment, so that the arrangement resembles athree panel make-up mirror.

FIG. 9 is an illustration examples of possible configurations of arraysfor various treatment applications.

FIG. 10A-10B illustrate examples of individual LEDs in accordance withthe present invention and the angle of divergence of an emitted beam.

FIG. 11A-11C illustrates three different examples of patterns of lightenergy density on the field of illumination. The irradiation illustratedin FIG. 11B is relatively uniform and homogeneous. The irradiationillustrated in FIG. 11C is relatively uneven and non homogeneous.

FIG. 12 is a shows a technique for coupling the light output of anoptoelectronic device with an optical fiber.

FIG. 13 is a schematic drawing of the output of several individualoptoelectronic devices collected into a single beam.

FIG. 14A illustrates an example of use on skin diseases such aspsoriasis (a proliferative skin disorder that is known to respond toultraviolet light therapy).

FIG. 14B illustrates applications of the present invention to delay,stimulate or inhibit hair growth.

FIG. 14C illustrates the treatment of scars or stretch marks is alsopossible.

FIG. 14D shows the use of LED light in conjunction with an exogenouschromophore to diminish oil gland activity or to reduce acne.

FIG. 14E illustrates an example of illumination by the LED of nervefibers where nerve injuries need to be stimulated, regenerated, orhealed.

FIG. 14F illustrates nail disorders with fungal infection, to be treatedin accordance with the present invention.

The detailed description of a preferred embodiment of the presentinvention will be made with reference to the accompanying drawings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following detailed description is of the best presently contemplatedmode of carrying out the invention. This description is not to be takenin a limiting sense, but is made merely for the purpose of illustratingthe general principles of the invention. The scope of the invention isbest defined by the appended claims.

In a preferred embodiment, the present invention is directed to aprocess for dermatological treatment. Such a treatment may include thephotomodulation of hair follicles, hair bulb, hair bulge, stem cells andthe surrounding tissue to produce temporary or permanent stimulation ofactivity of surrounding tissue or supporting tissue in human ormammalian skin, of some or all of the hairs. In a preferred embodimentthe process produces little or no permanent injury or damage to nearbyskin tissue. Primarily, only the hair and immediately surrounding tissueare affected. For purposes of the present invention, any recitation ofthe hair also includes the hair follicle, bulb, bulge, stem cells andother components of the supporting dermal structure that supports hairgrowth.

In a process according to one embodiment of the present invention, anagent may be selected which is capable of penetrating the hair ducts andattaching, bonding or otherwise becoming incorporated into the hairshaft, hair follicle, hair bulb, hair duct cells, or stem cellscollectively referred to hereinafter as hair growth structures. Theagent may be characterized as an active agent in that it performs afunction in addition to simply occupying or contaminating the space inthe ducts surrounding the hair shaft. The agent may have sufficientoptical absorption of a wavelength (or a combination of wavelengths) ofa coherent or non-coherent light source which can penetrate the skinadequately to be absorbed by the target agent or the new agent-tissuecomplex or it may in some other way directly or indirectly enhance thestimulation of hair growth structures.

The area of skin overlying where the hair duct is located may becleansed. After the skin is cleansed, the skin may be treated to improvepermeability. This may be accomplished, for example, by treating theskin with steam or a hot moist towel to hydrate the skin and hair orremoving a portion of the stratum corneum through various means known inthe art, exemplary of which is microdermabrasion.

The agent may be applied in sufficient quantity and in suitable form tobe incorporated into the target tissue in adequate or optimal amounts toallow the production of the desired tissue effect, as described in U.S.Pat. No. 6,283,956 which is hereby incorporated by reference in itsentirety.

Excess agent may be removed, neutralized, inactivated, decolorized,diluted or otherwise altered so that residual contamination of the skinby such excess agent is either (a) absent and does not interact with thelight or energy source, or (b) present in such small quantity that itprovides no clinical effect.

Delivery of the desired agent into the target tissues, ducts, or nearbysebaceous oil glands may be enhanced, facilitated or made possible bythe use of enzymes capable of altering the structure, permeability, orother physical characteristics of the stratum corneum or by the use ofultrasound or phonophoresis either for penetration into the gland orsurrounding target tissues or, once penetrated, to cause the release ofthe agent from the encapsulated delivery device such as liposomes,polymers, microspheres, etc. so as to cause penetration or attachment ofthis active agent. Ultrasound may be used therapeutically to interactdirectly with the agent or the agent-tissue complex to produce thedesired damaged target tissues (to be used alone or in combination withlaser or non-laser light sources). Microdermabrasion may also be used topermit greater penetration of the skin, wherein the upper epitheliallayers are removed. These layers create a natural barrier to thepermeability of the skin and. by their removal, penetration of the skinby topical agents is facilitated. This method may be further enhanced byusing ultrasound, alone or in combination with alteration of the stratumcorneum, to further improve the performance of topical compositions. Amore detailed description of several aspects of the use of ultrasoundmaybe found, for example, in the applicant's U.S. Pat. No. 6,030,374 for“Ultrasound Enhancement of Percutaneous Drug Absorption” which is herebyincorporated by reference in its entirety. Further, methods of improvingthe penetration of topical agents through the stratum corneum are morefully described in applicant's copending U.S. application Ser. No.09/876,157, which is hereby incorporated by reference.

Although preferred embodiments of the present invention may use LEDs,ultrasound and/or laser or light energy from sources such aslight-emitting diodes, the present invention is not limited to the useof these energy sources. Other sources of energy, including (withoutlimitation) microwave energy and radio frequency energy or electricalstimulation or magnetic fields/forces may also be used. Exemplary ofknown light sources are fluorescent lights, flashlamps, filamentouslights, metal halide lights, halogen lights, etc. One skilled in the artwill recognize that any light source capable of emitting electromagneticradiation at a medically useful wavelength, as described herein,directly, or by means of optical filtration, is within the scope ofsuitable light sources according to the present invention. For purposesof the photomodulatory and photothermal treatment methods described, anysource capable of emitting light having a wavelength from about 300 nmto about 1600 nm, or producing electromagnetic radiation which isfiltered or otherwise altered to exposure the skin, a topicalcomposition, or other component of the present treatment regime to awavelength of light in the aforementioned range is medically useful.

The targeted skin may be exposed to one or more wavelengths of LED,laser or non-laser light such as filtered filamentous sources orfluorescent sources alone or in combination with single or multiplefrequencies of ultrasound. The light source may be polarized orunpolarized, as can any light source described herein in accordance withthe present invention. A variety of parameters may be used (includingpulse duration, energy, single or multiple pulses, the interval betweenpulses, the total number of pulses, etc.) to deliver sufficientcumulative energy to interact with the agent or tissue complex. Oneembodiment of the invention, this results in the stimulation of hairgrowth or the supporting skin tissue through photomodulatory means,photothermal means electrical stimulation, or combinations thereof.Alternatively, proper exposure to certain wavelengths of light,combinations of certain wavelengths of light, such light sources eitheralone in combination at various intensity levels, with and withouttopical compositions to enhance the penetration of the light, arecapable of photostimulation of hair follicles, glandular and ductactivity, etc. resulting in the stimulation of hair growth. Ultrasoundmay also be used to preheat the target structures or the entire skin.Further for treatment over a broad area of human skin, the light sourcemay be diffused through a device such as a holographic diffuser; or,alternatively, the light source may be comprised of an array ofindividual emitters such as the multi-panel array of LEDs illustrated inFIG. 3. Further increasing the number of panels to more precisely followthe contours of the portion of the patient receiving treatment producesmore uniform exposure and improved results. For example, a collection ofpanels that can be manipulated to provide even exposure to the entireface or scalp of a patient will provide excellent results when thefacial area is targeted to reduce facial hair or when the scalp istreated to stimulate hair growth. For localized treatment, smallerarrays or individual LEDs, such as in the hand held devices. A collageof such devices is illustrated in FIG. 9. Since LED sources aregenerally considered “insignificant risk devices”, no medicalsupervision is required and these devices may be used by the patient forat-home treatment or as part of an ongoing skin-care system afterreceiving treatment by a physician.

The topical agent may be incorporated into the target tissue by avariety of mechanisms. These mechanisms include, but are not limitedto: 1) physical incorporation into target tissue cells while leaving thechemical structure essentially unaffected, or 2) undergoing a chemicalreaction resulting in a new agent-tissue complex which then becomes atarget for energy absorption.

The process may be a single or multi-step process and may involve theuse of cofactors, catalysts, enzymes, or multiple agents which interactto ultimately become or create an active agent or agent-tissue complex.

Agents may include, without limitation, the following compositions andderivatives and analogs thereof: hair dyes, vegetable dyes, foodcoloring, fabric dyes, tissue stains, shoe or leather dyes, other plantproducts (such as flavonols, chlorophyll, copper chlorophyllin, bacteriachlorophylls, carotenoids, enzymes, monoclonal antibodies, anyimmunological agent, genetically engineered agent, benign infectiousagents, whether naturally occurring or genetically engineered (e.g. thebacteria that normally reside on the skin such as acne bacteria, etc.),antibiotics, agents which attach to sebocytes in the sebaceous gland orduct cells directly, whether by topical or systemic agents that localizein these target tissues, including antibodies or antibody-chromophorecompounds of these structures. The preceding list is illustrative andnot exhaustive of those agents suitable for use in accordance with thepresent invention. In general, the topical agent chosen will havecertain absorption characteristics that augment the penetration of theradiation to the tissue targeted for treatment, i.e., or increasingblood circulation to the structures. Additional agents that are mostbeneficial for stimulating hair growth have been found to includevasodilators, inhibitors of 5-alpha reductase (most preferably type 2,although type 1 is considered beneficial as well, stimulators oractivators of ornithine decarboxylase, stimulators or activators ofvascular endothelial growth factor (VEGF), PDGF, HGF, KGF, IGF, EGF,TGF-alpha, TGF-beta, FGF-alpha, FGF-beta, inhibitors of protein kinaseC, stimulators or activators of adenylate cyclase, skin irritants,curcumin, mineralocorticoid receptor antagonists, and the various meansknown in the art for increasing intracellular Ca²⁺ or any means ofinhibiting MMP, AP-1, c-Jun in combinations with light. While theprimary method of delivery for such agents is through topical contactwith the skin, in some instances it is preferable or advantageous toadminister the composition orally or by injection or other systemicroute.

Most preferable are topical compositions that stimulate or modulateomithine decarboxylase or vascular hair related growth factors orsignaling molecules.

Agents may be delivered in pure form, in solution, in suspension, inemulsions, in liposomes, in synthetic or natural micro spheres,microsponges or other known microencapsulation vehicles, alone or incombination or in other forms common or known to those skilled in art oftopical and oral delivery. This list of the forms of the agents isillustrative and not exhaustive. Those skilled in the art will recognizethat there are a wide variety of forms for the delivery of these typesof compositions suitable for use in accordance with this invention.

The process may include an application of an active agent and treatmentwith an energy source as a single treatment. Alternatively, treatmentwith an energy source may be delayed for hours or days after applicationof an active agent. Application of an active agent may be performed orapplied at another location, such as patient's home, prior to the energytreatment.

After an energy treatment has occurred it may be desirable in somesituations to remove, neutralize, decolorize or otherwise inactivate anyresidual active agent. In other situations, continued application toreplenish depleted chromophore may be desirable.

One hair reduction treatment process uses a solution of graphite in acarrier solution and a Q-switched 1064 nm ND: Y AG laser. The solutionmay be applied to the skin which is then treated with the laser usingknown parameters. It may be preferable to use a high repetition rate andmove the laser hand piece slowly enough that pulses are “stacked” in onespot for several pulses before the hand piece is moved to an adjacentspot. It has been found that there is a stair-step like effect ofincremental temperature rise in the sebaceous glands with the second andthird pulses versus a single pulse. A faster repetition rate also tendsto help build the heat up faster, and to higher levels. This tends toproduce the maximum heat (which is desirable, as long as the heat staysconfined to the sebaceous glands and the immediately adjacent supportingtissues). Since this effect occurs substantially simultaneously withother destructive effects of the process, the damage to hair structurestends to be enhanced. Unlike carbon exploded particles on light impact,the dyes and similar agents may actually remain absorbing for a brieftime until they reach a critical temperature at which time they aredestroyed or become non absorbers, thus acting as a sort of heat sinkfor a brief time, allowing more heat to accumulate than with carbonsolutions and short pulsed Q-Switched lasers. Safety remains at aboutthe same level, since dye related damage tends to be confined to targettissues. There is no appreciable change in patient treatment time.

Another preferred embodiment uses a longer pulsed laser in the 750nm-1000 nm range and appropriate parameters to achieve the desiredtissue damage goal.

Another embodiment uses a tissue dye which attaches to, or isincorporated into, a target cell and surrounding tissues. The targettissue may be illuminated with a multiwavelength non-laser light sourceusing appropriate parameters to achieve the desired tissue stimulationgoal.

Another embodiment uses a light source which is well-absorbed by themelanin naturally present in skin and undyed darker hairs. Natural orsynthetic melanin or derivatives thereof will be well-absorbed by thesame wavelength of light (or alternatively two or more wavelengths, onefor melanin and one or more for the dye). This tends to benefit peoplehaving darker skin or tanned skin, by allowing lower treatment energy.For example, a diode laser or LED or non-laser light source couldproduce a continuous or pseudo-continuous beam of light energy usingpulse durations as long as seconds at a wavelength which is absorbed bythe light-activated chromophore or naturally occurring synthetic melanindelivered topically to the hair and supporting dermal structure. A pulseduration on the order of between about one and thirty seconds appears tobe preferable. This also tends to be a much longer time than is used inmost systems in use today.

Another embodiment uses an agent which facilitates cavitation shockwaves or a thermal effect or both. This preferentially stimulates thetarget tissues while minimizing damage (or other adverse effects) onsurrounding non-target tissues. This may be used with very short pulsedlasers or light sources or with ultrasound alone.

In one embodiment a process in accordance with the present invention maybe used to provide short or long-term thickening darkening orstimulation of growth of hair. An active agent may be physically orchemically or immunologically incorporated into cells of the hair ornearby sebaceous (oil) glands, ducts, or supporting tissue, naturallyoccurring light activated chromophores. Some acne bacteria may notinhabit all sebaceous structures and other strains may not producenative porphyrins to target with light. Other acne bacteria may belocated deeper than 400 nm to 420 nm light can adequately penetrate,thus treatment with light alone may be only partially effective inclinical treatment or longer deeper penetrating wavelengths such asyellow or red visible or infrared light may be used alone or incombination with the 400-420 nm blue visible light. Since acne bacteriaare anerobic, that is they grow in the absence or relative absence ofoxygen, introducing oxygen into the sebaceous apparatus or gland istoxic or destructive to these bacteria. Thus a light activated agentreleasing oxygen or a topical adjunctive oxygen releasing or generatingagent will also improve acne reduction treatment. Improvement in skindisorders may be a direct or indirect result of the application of theagents in this process, as may reduced oiliness of the skin, reducedsize or diminished appearance of pores, etc. The present invention isalso useful for treating enlarged pores, oily skin, stretch, marks,wound healing (alone or in combination with growth factors) and otherdisorders where there is no active acne-related disorder. Other similardisorders such as folliculitis which involve the pilosebaceous (hair/oilgland) unit may also be treated using the present invention. The presentinvention may also be used to reduce perspiration, sweating, orhyperhydrosis from eccrine (sweat) glands or apocrine glands. Apreferred embodiment of the present invention may be used to treat otherskin disorders such as, for example, viral warts, psoriasis,precancerous solar keratosis or skin lesions, hyperhydrosis/excessivesweating, aging, wrinkled or sun damaged skin, and skin ulcers(diabetic, pressure, venous stasis).

Scarring is commonly seen as a consequence of disorders, diseases, ordysfunctions of the sebaceous or hair apparatus. Scarring may consist ofone or more of the following: raised hypertrophic scars or fibrosis,depressed atrophic scars, hyperpigmentation, hyperpigmentary redness ortelangectasia and hair follicle related scarring. Photomodulatory,photochemical, or photothermal treatments alone, or in combination withexogenous or endogenous chromophores, or combinations thereof, can beused simultaneously, sequentially, etc., as described herein for thetreatment of various disorders, diseases, or dysfunctions. Further, asherein described, the term photomodulation refers to the treatment ofliving tissue with light along, heat emitted by a light source, orlight-activated chemical compositions, or any combination thereof.Falling within the scope of photomodulatory treatments are photothermaltreatment, photoactivation, photoinhibition, and photochemical treatmentof living tissue and, in particular, hair related structures withinhuman or animal skin. Further, electromagnetic emitters of the presentinvention can fall into three categories: those which emit light in thevisible spectrum and are useful for photo activation and photoinhibitionphotomodulatory process; those that emit light in the ultravioletspectrum and are also useful for photoactivation and photoinhibitionphoto modulatory process; and those that emit light in the infraredregion and permit photomodulation treatment to be carried out throughphotothermal means, i.e., heat activation of the exogenous chromorphore,living cells or tissue, or both.

A preferred embodiment of the present invention may use variousmicroencapsulation processes to deliver active agents. If the diameterof the micro encapsulations is less than five microns, then there may berelatively site specific delivery into the structures. If the diameterof the microencapsulations is in the range of about one micron, then theactive agents may be delivered with a more random distribution betweenthe hair ducts and the oil glands. If the diameter of themicroencapsulations is larger, on the order of about 20 microns orgreater, then delivery will tend to be restricted primarily to the skinsurface. Smaller diameters such as nano particles may be desirable. Themicro encapsulations may be synthetic or natural. If ultrasound is usedto enhance penetration, then the diameters and ultrasound treatmentparameters may need to be adjusted according to the applicableprinciples which allow the estimation of the optimal ultrasoundparameters for driving small particles into the skin, skin appendages orskin orifices. Larger molecules or proteins (including many reveuantgrowth factors) that cannot penetrate intact skin may be delivered byremoving a portion of the stratum corneum or using ultrasound (or both)to enhance delivery.

Microencapsulation may be used to improve delivery of known agents suchas chlorophyll, carotenoids, methylene blue, indocyanine green (ICG) andparticles of carbon or graphite. A known technique for using a laser toproduce a wavelength that may be absorbed by indocyanine green for ahair removal treatment process is described, for example, in U.S. Pat.No. 5,669,916, which is incorporated by reference. It has been foundthat by using smaller particles and putting the smaller particles intomore uniform diameter microencapsulations, more site specific or uniformtargeting may be achieved. A preferred formulation may includeindocyanine green or other dyes or agents to form a lipid complex whichis fat-loving (lipophilic). The delivery and clinical effects of agentsand dyes such as indocyanine green dye may be refined and enhanced byselecting a carrier or encapsulation having a diameter that increasesthe probability of preferential delivery to a desired space, and/or thatenables interaction with ultrasound to thereby increase the probabilityof preferential delivery, and/or that selectively attaches to the hair,duct, supporting tissues, hair shaft itself or bacteria, yeasts, orother organisms residing within these tissues.

Indocyanine green dye is presently in medical use, appears to berelatively benign, may be activated by red visible lasers, or othersource of monochromatic or multichromatic light, (in the 800 nm range)may penetrate deeply enough to reach the oil glands, is used for legvein and hair removal, and is relatively safe, cheap, and reliable. Aknown technique for using a laser to produce a wavelength that may beabsorbed by indocyanine green for use in a leg vein treatment process isdescribed, for example, in U.S. Pat. No. 5,658,323, which isincorporated by reference. Methylene blue has also been used accordingto the present invention with good success.

The microsponges containing the active agent may selectively attach, orat least have a chemical affinity for, some part of the oil gland. TheICG may be conjugated with lipids, which would then have an affinity forthe hair by oil glands. Alternatively, the attachment may occur afterthe active agent is released from the micro sponge, either passively orby attractive or chemical forces. In the case of some microencapsulationcarrier vehicles, release may occur after disruption of the vehicleintegrity itself, possibly by ultrasound or laser or light or otherenergy source or perhaps a chemical reaction.

In a preferred embodiment the ICG may be mixed with lipids, or put intomicrosponges (a.k.a. microspheres), and then applied to the skinsurface, allowed to sit for a time. Excess dye may be removed, and thenthe area may be treated with laser light at about 800 nm, between about0.1 and 100 millisec pulses and around 1.0 microJoule/cm²-10.0Joules/cm². A treatment session lasting from about 1 second to about 15minutes is preferred.

U.S. Pat. No. 5,817,089 specifies “particles having a major diameter ofabout 1 micron”. It has been discovered, however, that such diametersmay not be optimal. A 1993 Pharmaceutical Research journal article byRolland et al describes an acne treatment wherein a topical acne drug isdelivered with less irritation by putting the drug into syntheticpolymer microsphere sponges. This article reported that an optimaldiameter for site-specific delivery into sebaceous oil glands in theskin was about 5 microns, and that 1 micron particles randomly deliveredto the hair follicle and stratum corneum.

Most agents may not inherently be the optimal size. However, virtuallyany agent may be preferentially delivered to the sebaceous glands byeither synthetic microspheres, or liposomes, or albumen microspheres, orother similar “delivery devices”.

In a preferred embodiment for stimulation of hair growth, graphiteparticles having an average diameter of about one micron or less may becarried in delivery devices, such as microsponges. The microsponges maythen be suspended in a lotion. Ultrasound may be used to drive theparticles into the skin. The optimal ultrasound parameters may be basedon the outside particle diameter (especially if particles are uniform).Selective delivery of the particles to hair and perhaps to oil or glandsweat glands may be improved.

Use of such applications could enable selective delivery of agents whichstimulate hair growth, or other hair treatments, to thicker, darken,color, lengthen hair where the encapsulation diameter was used, with orwithout ultrasound, to preferentially deliver, and ultrasound atdifferent parameters or light or laser was used to release (notnecessarily to activate or interact).

These techniques may be applied to many other agents in addition to ICGand graphite lotions. The term “encapsulated delivery device” is usedherein as a generic term which encompasses all such possible items.

Pressure may be used to impel particles (i.e., graphite, carbon, orother active agent or skin contaminant particulates) into the skin,either in the spaces between the stratum corneum, into the hair ductsand hair follicles, hair bulge, hair stem cells (i.e., the 25 hairstructure), the sebaceous oil glands, or other dermal structures. Airpressure or other gases or liquids may be used to enhance delivery orincrease the quantity of delivered agent. A known technique for using anair pressure device for removing skin surface is described, for example,in U.S. Pat. No. 5,037,432, which is incorporated by reference.

Ultrasound may be used to physically deliver hair dye and to enhancepenetration into the hair shaft itself (see, for example, U.S. Pat. No.5,817,089, incorporated herein by reference). The use of ultrasound tophysically drive graphite particles down for the treatment of unwantedhair or acne appears to have been suggested in the prior art. However,the applicant is aware of no prior art disclosure or suggestion of: (1)the use of ultrasound to enhance the penetration of an agent into thehair shaft itself, or into surrounding cells; (2) the use of ultrasoundto drive graphite particles into spaces between the stratum corneum toenhance the effects of a skin peel process (which physically removes aportion of the outer layers of the skin surface); or (3) physicallyremoving the hair by methods such as waxing or pulling and theninjecting the treatment composition, i.e., the chromophore or othertopical composition, into the sebaceous gland or duct. Such methods arecontemplated in one embodiment of the invention.

Further, it is contemplated that yellow light can be used to normalizemelanin production in the skin. While not wishing to be bound by theory,it is believed that light in the yellow portion of the spectrum 590 nmto 660 nm red enhances the release of intermediary chemical signals thatcauses melanocyte cells to function more normally. That is, if themelanocyte cells are not working they begin to make pigment again; andif the melanocyte cells are producing too much pigment or producing thewrong configuration of pigment, they are stimulated to producing pigmentin the correct amount and configuration.

A known skin peel process may be improved by using ultrasound to openintercellular spaces in the outer stratum corneum layer of the skin viacavitation. Then an active agent may be driven in further with the sameor similar ultrasound. Fibroblast stimulation may be optimized with bothtopical agents that are applied afterwards (while the skin is stillrelatively permeable) and also with additional low level lightstimulation.

The processes described above may be used to deliver two differentagents, either serially or simultaneously. The two agents may then beactivated by the light source together to work synergistically, or tocombine and then have an effect, or to deliver two different agents thatmay be activated simultaneously or very closely in time. Two differentlight sources or wavelengths may be used serially or simultaneous tohave different effects such as treating active acne lesions and alsoacne scarring; treating acne rosacea lesions and allows rosacea bloodvessels or telangectasia; or using photothermal means for active acneand nonthermal photomodulation for treating acne scarring or skinwrinkles.

Two entirely different laser, LED, or light beams may be deliveredsubstantially simultaneously through the same optics at differentparameters. For example, one beam may be delivered primarily to releaseor to activate or precondition, and a second beam primarily to treat.Additive effects may be achieved by using two beams at the same time,such as the use of blue light with a wavelength of approximately 400 nmand red light with a wavelength of approximately 600 nm. For example, aknown process for skin peel and hair reduction may be optimal at 1064 nmfor safety and for treating all skin colors, but other wavelengths maybe better to achieve a low level laser stimulation of fibroblasts. Acnereduction is achieved by this process, as well, using lasers or LEDS asthe low-level light source at a wavelength chosen according to theabsorption spectrum of the topical composition used. Particularlypreferred for topical compositions are those comprising hair or vasculargrowth factors or hormones and derivatives thereof, and mixturesthereof, as well as derivatives, analogs, and genetically engineeredforms of such agents as well ornithine decarboxylase stimulators.

A hand-held device containing the low-level light source may be used tophotomodulate or photothermally activate, or both, the living tissue oractive ingredient in the topical composition, or both, for skin peel,hair growth stimulation, or hair thickening, or increase hair density,hair growth rate, restore or alter hair pigmentation, hair shaftthickness, and either simultaneous or synchronized sequentially in timeto deliver another wavelength that may be optimal in view of theabsorption characteristics of the patient's fibroblast spectrum, thehair structure or the absorption spectrum of the topical composition. Inone case it may also be the best wavelength to stimulate mitochondria orfibroblasts. In another case it may allow selection of a melanin or dye(or other agent) having very strong affinity for the sebaceous gland orhair structure and a very strong absorption at the wavelength used fortreatment. The various embodiments of the invention described herein arealso well-suited to the stimulation, proliferation, and growth of hairimplants and transplants.

There are a wide variety of different operating parameters that maycomprise conditions effective to produce beneficial cellular effectssuch as triggering cellular regeneration or photoactivation orphotostimulation of hair growth. Further photothermal modulation of thehair and surrounding tissue can be accomplished via the same means asdescribed above, although the operating parameters may vary. Thedifference being that photothermal treatment uses heat to induce minorto moderate amounts of thermal injury to the hair or surround tissue tostimulate the activity of the target tissue.

Exogenous chromophores are substances which absorb light orelectromagnetic radiation in at least one narrow band of wavelengths andassist with the treatment method and system of the present invention byapplying them to an area of the skin to be treated. Selection of theexogenous chromophore is determined by the absorption spectra of thechromophores and is dependent on the wavelength of the narrowband multichromatic emitter used for treatment. In accordance with a preferredembodiment of the invention, the chromophore will aid in treatment byenabling at least the dominant or central wavelength of the narrowband,multichromatic radiation to penetrate at least the stratum corneum layerof the skin and permitting the photomodulation or photothermal injury ordestruction of living tissue, hair, duct, or supporting tissue in andbelow the stratum corneum. In some instances, the photomodulated tissuecan be below all of the epithelial layers of the skin.

Some examples of possible operating parameters may include thewavelengths of the electromagnetic radiation to which the living tissuecontaining cells to be regenerated, stimulated, inhibited, or destroyed,the duration of pulses (pulse duration) of the electromagneticradiation, the number of pulses, the duration between pulses, alsoreferred to as repetition rate or interpulse interval. Intervals betweentreatments can be as long as hours, days, weeks, months, etc.; and thetotal number of treatments is determined by the response of theindividual patient. Further, treatment regimens using a combination ofmore than one wavelengths either simultaneous or in sequence may beused. As well, the energy intensity of the radiation as measured at theliving tissue (typically measured in Joules per centimeter squared,watts per centimeter squared, etc.), the pH of the cell, tissue or skin,the skin temperature, and time from application to treatment with alight source, if used with exogenous chromophore (which can be topical,injected, driven in with ultrasound, or systemic) is determined by thenature of the treatment and is further illustrated in the Examples.

Wavelength—Each target cell or subcellular component, or molecular bondtherein, tends to have at least one unique and characteristic “actionspectrum” at which it exhibits certain electromagnetic or lightabsorption peaks or maxima FIG. 6, for example, shows the absorptionspectrum of one line of human fibroblast cells in monolayer tissueculture. Different cell lines (of the same cell—for example fibroblastsfrom 3 different patients) exhibit some differences in their absorptionspectra and thus using narrow band multichromatic light (rather thanmonochromatic light) is also useful in producing the optimal clinicaleffect. When these cells or subcellular components are irradiated withwavelengths corresponding to the absorption peaks or maxima, energy istransferred from the light photon and absorbed by the target. Theparticular features of the delivered energy determine the cellulareffects. The complexity of these combinations of parameters has producedmuch confusion in the prior art. Basically, the wavelength shouldroughly correlate with an absorption maxima for the target cell orsubcellular component or tissue, or exogenous chromophore. In some casesit may be desirable to target more than one maxima—either simultaneouslyor sequentially on the same or different treatment dates. The presenceof multiple maxima action spectra are common for a given cell orsubcellular component or exogenous chromophore and different wavelengthmaxima irradiation may produce different results.

If the wavelength band is overly broad, then the desired photomodulationeffects may be altered from those intended. Consequently, use of broadband noncoherent intense light sources may be less desirable than thosespecified for use with the present invention, in contrast to the use ofmultiple narrowband emitters. The laser diodes are also multichromaticwith narrow wavelength bands around a dominant band, i.e., they arenarrowband multichromatic devices—devices which emit electromagnetic ina narrow band of radiation either symmetrically or asymmetrically arounda dominant wavelength. For purposes of the present invention, any devicethat emits electromagnetic radiation in a bandwidth of +/−about 1000nanometers around a dominant wavelength can be considered to be anarrowband, multichromatic emitter. LEDS, while not monochromatic, emitin such a narrow band as to be considered narrowband multi chromaticemitters. The narrow band allows photons of slightly differentwavelengths to be emitted. This can potentially be beneficial forcreating certain desirable multi photon interactions. In contrast, mostcommercial lasers emit light at a single wavelength of light and areconsidered monochromatic. The use of lasers, according to the prior art,has relied upon the coherent, i.e., monochromatic, nature of theirelectromagnetic emissions.

Wavelength may also determine tissue penetration depth. It is importantfor the desired wavelength to reach the target cell, tissue or organ.Tissue penetration depth for intact skin may be different than thetissue penetration depth for ulcerated or burned skin and may also bedifferent for skin that has been abraded or enzymatically peeled or thathas had at least a portion of the stratum corneum removed by any method.It is also important to penetrate any interfering chromophore that alsoabsorbs at this same wavelength (e.g. dark ethnic skin, plastic Petriedishes for tissue or cell culture, etc.). It is important to penetrateany tissues or organs in its pathway.

For example, light having a dominant wavelength emission in the range ofabout 400 nm to about 420 nm has such a short wavelength that not allsebaceous glands or acne cysts can be effectively treated due to thelimited depth of penetration of the radiation, whereas light having awavelength of about 600 nm to about 660 nm can more easily penetrate toa greater depth, if treatment of the lower dermal layers or even deeperis desirable. Accordingly, the selection of the dominant wavelength ofthe radiation emitter is also dependent on the depth of treatmentdesired. The selection of the proper wavelength is one of thesignificant parameters for effective use of the present invention, butothers are important as well. To achieve treatment according to thepresent invention, the following are the relevant parameters that mustbe chosen and applied to the emitter for electromagnetic radiation inorder to photomodulate any cell signaling pathways leading to thestimulation or inhibition of gene expression which directly orindirectly modulates hair growth. Specifically, these parameters are:

Energy Density—The energy density corresponds to the amount of energydelivered during irradiation and is also referred to as energy intensityand light intensity. The optimal ‘dose’ is affected by pulse durationand wavelength—thus, these are interrelated and pulse duration is veryimportant—in general high energy produces inhibition and lower energyproduces stimulation.

Pulse duration—The exposure time for the irradiation is very criticaland varies with the desired effect and the target cell, subcellularcomponent, exogenous chromophore tissue or organ. (e.g. 0.5 microsecondsto 10 min may be effective for human fibroblasts, though greater orlesser may also be used successfully).

Continuous Wave (CW) vs. pulsed—e.g. the optimal pulse duration isaffected by these parameters. In general, the energy requirements aredifferent if pulsed mode is used compared to continuous (CW) modes.Generally, the pulsed mode is preferred for certain treatment regimenand the CW mode for others.

Frequency (if pulsed)—e.g. higher frequency tends to be inhibitory whilelower frequency tends to be stimulatory, but exceptions may occur.

Duty cycle—This is the device light output repetition cycle whereby theirradiation is repeated at periodic intervals, also referred to hereinas the interpulse delay (time between pulses when the treatment sessioncomprises a series of pulses).

Suitable active agents for use in topical compositions applied to theskin in accordance with the present invention include one or more ofVitamin C, Vitamin E, Vitamin D, Vitamin A, Vitamin K, Vitamin F, RetinA (Tretinoin), Adapalene, Retinol, Hydroquinone, Kojic acid, a growthfactor, Echinacea, an antibiotic, an antifungal, an antiviral, ableaching agent, an alpha hydroxy acid, a beta hydroxy acid, salicylicacid, antioxidant triad compound, a seaweed derivative, a salt waterderivative, algae, an antioxidant, a phytoanthocyanin,epigallocatechin-3-gallate, a phytonutrient, plankton, a botanicalproduct, a herbaceous product, a hormone, an enzyme, a mineral, agenetically engineered substance, a cofactor, a catalyst, an anti agingsubstance, insulin, trace elements (including ionic calcium, magnesium,etc), minerals, minoxidil, finesteride, a hair growth stimulatingsubstance, a hair growth inhibiting substance, a dye, a natural orsynthetic melanin, a metalloproteinase inhibitor, an inhibitor of AP-1or C-Jun or both, proline, hydroxyproline, an anesthetic substance,chlorophyll, bacteriochlorophyll, copper chlorophyllin, chloroplasts,carotenoids, phycobilin, rhodopsin, anthocyanin, and derivatives,subcomponents, immunological complexes and antibodies directed towardsany component of the target skin structure or apparatus, and analogs ofthe above items both natural and synthetic, as well as combinationsthereof.

In one embodiment of the invention, topical skin care formulations maybe used for altering the pH or acidity of the skin.

In addition to being an effective treatment method for reducing andeliminating the presence of common acne bacteria such as acnes vulgarisand for safely treating conditions such as pseudofolliculitis barbae,acne rosacea, and sebaceous hyperplasia, the present invention also hasapplication to the reduction of cellulite. Using any of the lightsources suitable for use as described herein, adipocyte cells can bephotomodulated. Modulation of adipocytes alone for fat reduction or toalter the condition termed cellulite can be made directly through deathof the adipocytes, through increasing their metabolic rate, decreasingtheir storage of lipid, lipolysis or rupture. Such modulation ordestruction can be accomplished through one or a combination of massage,vibration, ultrasonic cavitation, ultrasonic thermal heating, modulationof receptors or genes in adipocytes, modulation with any source orcombination of sources of electromagnetic radiation alone or incombination with exogenous chromophores or topically applied or injectedsubstances which stimulate or inhibit these processes. Photomodulationincreases the local microcirculation in the cellulite and alters themetabolic activity of the adipocytes and supporting cells. Enhancedlocal microcirculation, metabolism or enzymatic activity, orcombinations thereof, may be produced by photomodulatory means. Toenhance the treatment, any of the topical chromophores as previouslydescribed can be used or non-chromophoric compositions can be used inconjunction with any of the photomodulatory methods, includinglow-intensity light therapy. Further photothermal means may be used todestroy adipocyte cells alone or in combination with photomodulatorymeans, with or without the use of exogenous chromophores.

Many living organisms—both animals and plants—have as one of their majordefense mechanisms against environmental damage to their cells and DNArepair system. This system is present in many if not all livingorganisms ranging from bacteria and yeasts to insects, amphibians,rodents and humans. This DNA mechanism is one which is involved inprocesses to minimize death of cells, mutations, errors in copying DNAor permanent DNA damage. These types of environmental and disease anddrug related DNA damage are involved in aging and cancer.

One of these cancers, skin cancer, results from ultraviolet light damageto the DNA produced by environmental exposure to natural sunlight.Almost all living organisms are unavoidably exposed to sunlight and thusto these damaging UV rays. The damage which is produced is a change inthe structure of the DNA called pyrimidine dimers. This causes the DNAstructure to be altered so that it cannot be read or copied any longerby the skin cells. This affects genes and tumor development and properfunctioning of the immune system.

An enzyme called photolyase helps to restore the original structure andfunction of the damaged DNA. Interestingly photolyases are activated bylight to then act to repair the DNA damaged by ultraviolet light. In thedark it binds to the cyclobutane pyrimidine dimmer created by the UVlight and converts it into two adjacent pyrimidines (no dimer connectingthese any longer) and thus the DNA damage is repaired. This directreversal of DNA damage is called “photoreactivation”. The photolyaseupon exposure to blue light absorbs the light energy and uses thisenergy to ‘split’ the dimer and thus restore the normal DNA structure.Other mechanisms of DNA repair exist as well.

The photolyase repair mechanism is not well understood at present, butnaturally occurring or synthetic or genetically engineered photolyasefrom essentially any living organism source can be utilized for otherorganisms including human and veterinary and plant applications. DNAdamage produced by factors other than ultraviolet light may also berepaired including, but not limited to, such factors as otherenvironmental damage or toxins, radiation, drugs, diseases, chemotherapyfor cancer, cancer, microgravity and space travel related damage, and amyriad of other causes.

Environmentally damaged skin and DNA can be treated with topicalendonuclease compounds with, or without, the assistance ofphotomodulation. Preferably, penetration enhancing treatments such asultrasound and others recited herein are used to maximize skinpenetration of the endonuclease compounds.

The use of such naturally derived or artificially created or geneticallyengineered photolyase enzymes, endonuclase enzymes, or related enzymesor other proteins functioning for DNA or RNA repair have a wide varietyof applications. For example, the ability to treat skin damaged bysunlight/ultraviolet light of disease and to repair, reverse, diminishor otherwise reduce the risk of skin cancer could be used either as atherapeutic treatment or as a preventive measure for people withseverely sun damaged skin, with precancerous skin lesions, or with skincancer.

This principle applies not only to skin cells and skin cancer but to avery broad range of skin and internal disorders, diseases, dysfunctions,genetic disorders, damage and tumors and cancers. In fact potentiallyany living cells might have beneficial effects from treatment withphotolyase or similar proteins in combination with light therapy. In oneembodiment of the invention, the repair of damage to hair supportingstructures may help to restore not only hair growth but also hairtransplant growth and to reverse graying of hair.

While in nature the light to activate the photolyase typically comesfrom natural sunlight, essentially any light source, laser and nonlaser, narrow band or broader bandwidth sources can activate thephotolyase if the proper wavelengths and treatment parameters areselected. Thus natural sunlight filtered through a selective sunscreencould be used to activate both native and exogenously appliedphotolyases. Another treatment option would be to apply the photolyaseand then treat with a controlled light source exposure to the properwavelength band and parameters. A wide variety of light sources could beutilized and the range of these is described elsewhere in thisapplication. For example a low energy microwatt narrow band butmultispectral LED light source or array with mixed wavelengths could beutilized. Particularly important is the wavelength produces by the lightsource and not the source. Those skilled in the art will recognize thatthere are many sources for electromagnetic radiation capable ofproducing the required wavelengths used in the various embodiments ofthe present invention.

Another embodiment is a filtered metal halide, halogen, or fluorescentlight source with a dominant wavelength of 415 nm +/−20 nm and anexposure of 1-30 minutes at 1-100 milliwatts output can be utilized.Such exposure would occur minutes to days after application of a topicalproduct containing photolyase. When used alone, the wavelength of light(in the blue portion of the visible spectrum) can be used to reduce skinwrinkles, repair photo aging in human skin and tissue, and activatenatural photolyases. Moreover, this wavelength can activate othernatural repair mechanisms to reduce vein and capillary visibility,normalize melanin and pigment product, and restore natural skincoloration.

Another example would be the repair of cells in the skin which haveenvironmental damage but instead of repairing the cells which lead toskin cancer the cells which lead to aging (photoaging) of the skin aretargeted for this therapy. In one embodiment, kin fibroblasts which havebeen sun damaged are treated with a photolyase and subsequently thephotolyase is photomodulated with blue light to set in motion the DNArepair mechanism of photolyase—that is photoreactivation. This allowsthe repair of the structure and thus the normal functioning of thefibroblast DNA thus allowing normal functioning and proliferation ofthese fibroblasts—which produce the proteins such as collagen andelastin and hyaluronic acid and matrix ground substance which cause skinto be firm and elastic and youthful in appearance—thus producinganti-aging or skin rejuvenation effects in the skin as well as improvingthe structure and healthy function of the skin.

Various cofactors which are involved in this photoreactivation processcan also be added either topically or systemically to further enhance orimprove the efficiency of this process. Other cofactors needed in theproduction of these proteins once the cells recover normal function alsomay be added topically or systemically to enhance the anti-aging or skinrejuvenation process. The delivery of both the photolyase and/or thecofactors described above can be enhanced by utilizing ultrasound toincrease skin penneability or to increase transport across the skinbarrier and into the skin and underlying tissues. Removal of a portionof the stratum corneum of the skin can also be used, alone or incombination with ultrasound, to enhance penetration and delivery ofthese topically applied agents. Additionally such methods of removing oraltering the stratum corneum can assist in penetration of the light orthe efficiency of same or allow use of lower powered light sourcesincluding home use devices such as battery powered LED sources.

A variety of sources exist for obtaining photolyases. These may includenative naturally occurring photolyases, compounds derived from otherliving organisms (that is one may use for example bacterially derived,or yeast derived, or plankton rederived, or synthetic or geneticallyengineered, etc., photolyases and use them in human skin for beneficialeffects thus not limited to same species derived photolyases. One knownphotolase is derived from Anacystis nidulans while others can be derivedfrom bacteria—yeast in fact protect themselves with a photolyase whichcan be used in humans, other microorganisms, plants, insects, amphibianand animal sources exist.

The photolyase enzymes function by light induced electron transfer froma reduced FAD factor to the environmental exposure produced pyrimidinedimers. The use of free radical inhibitors or quenchers such asantioxidants can also be used to supplement the photolyase therapy.Other light activated chromophores may be utilized with light sourcesand properly selected parameters to further enhance, stimulate,photomodulate, photoactivate or photoinhibit the target or supportingcells or tissue to promote the most effective treatment.

There are many causes of free radical damage to cells. In one embodimentwound healing can be accelerated by utilizing a combination ofantioxidants, cell growth factors, direct photomodulation(photoactivation) of cells, and photoreactivation through photolyases.Topical or systemic therapy with the proper cofactors and replacing anydeficiencies of co factors can further enhance wound healing. Forexample, a chronic leg ulcer wound could be treated with an antioxidantmixture of vitamin E, vitamin C and glutathione, as well as cofactorssuch as fatty acids and keto acids such as sodium pyruvate and low levellight therapy using and LED array with parameters selected tophotostimulate fibroblasts and epithelial cells could also receivetreatment with a photolyase and blue light therapy with or withoutaddition of various growth factors or subcomponents thereof thus greatlyaccelerating wound healing and healing wounds or burns that wouldotherwise not be treatable.

The potential uses of photolyases and light therapy include: thetreatment or repair or reverse nerve damage or diseases including spinalcord injuries and diseases; cancer or cancer treatment related problemsincluding radiation and chemotherapy; cervical dysplasia and esophagealdysplasia (Barrett's esophagus) and other epithelial derived cell ororgan disorders such as lung, oral cavity, mucous membranes, etc.; eyerelated diseases including but not limited to macular degeneration,cataracts, etc.

There are very broad health and commercial applications of photolyasemediated photorepair or photoreactivation of DNA (or RNA) damage withflavin radical photoreduction DNA repair via photomodulation or nativeor exogenously applied natural or synthetic or genetically engineeredphotolyases. The addition of topical. Oral, or systemically administeredphotolyases and also their cofactors or cofactors of the cells whose DNAis being repaired further enhance these applications. The use of oralantioxidant or photomodulation enhancing agents or synergistic cofactorsupplements can also enhance the effects of photomodulation in any bodytissue or cell treated. The enhanced delivery of such substancestopically via ultrasound assisted delivery, via alteration of the skin'sstratum corneum, and/or via special formulations or via special deliveryvehicles or encapsulations are yet an additional enhancement to thisprocess.

Additional research in this area has confirmed that people are affectedby certain colors. For example, there are studies showing that blue andgreen are the most calming for paint in medical offices; and otherstudies showing that different tints of sunglasses affect moods. Thecolors red and orange, i.e., the brain's perception of light having awavelength in the red and orange portions of the visible spectrum, havebeen shown to ‘agitate’ people.

There are also blue light photoreceptors such as cryptochrome whichphotomodulate the molecular clocks of cells and the biological orcircadian rhythm clocks of animals and plants. It is believed thatphotomodulation of the pineal gland in the human brain can be achievedthrough the present invention and, as a result, therapies relating tothe restoration and control of circadian rhythms is contemplated in oneembodiment of the invention, most preferably using blue light having awavelength of between about 390 nm and 490 nm. These are the mechanismsthat regulate responses to solar day/night rhythms in living organisms.These protein photoreceptors include vitamin B based crytochromes.Humans have two presently identified cryptochrome genes which can bedirectly or indirectly photomodulated (that is photoactivated or photoinhibited) and more as yet undiscovered receptors may exist in theretina or the brain which may be stimulated (or even directphotomodulation of the brain itself).

The clinical applications include treatment of circadian rhythmdisorders such as ‘jet lag’, shift work, etc, but also insomnia, sleepdisorders, immune dysfunction disorders, space flight related, prolongedunderwater habitation, and other disturbances of circadian rhythm inanimals. Particularly noteworthy among potential disorders arising fromdisruptions or alterations in circadian rhythms are indications thatcancers, and particularly breast cancer, may be avoidable throughcareful control of “body clock” or circadian rhythm patterns. Circadianissues also exist for many other living organisms including the plantkingdom. Low-intensity light therapy of the present invention can beadapted for use to treat these afflictions, as well.

Warts can be treated using exogenous or endogenous chromophores witheither photothermal or non thermal photomodulation techniques—or acombination of both. Examples of preferred embodiments of endogenouschromophores include the targeting of the vascular blood supply of thewart with either method. Another preferred embodiment is the use of atopically applied or injected or ultrasonically enhanced delivery ofsuch a chromophore into the wart or its blood supply or supportingtissues with subsequent photomodulation or photothermal activation ofthe chromophore. Immunological photomodulation may also occur with wartor infectious processes and such immunological photomodulation may beuseful in treating a special subtype of hair loss called alopecia areatathat is thought to be caused by immunologic disturbances in or aroundthe hair structures thus causing hair loss that is not age related andwhich can cause profound psychological distress and can even result inthe most severe cases in total loss of all body hair. Photomodulationcan be utilized to stimulate regrowth of the hair in such alopeciacases.

One such example would be that of a chlorophyll topical formulationsimilar to those described elsewhere in this application but of higherconcentration and vehicle and particle size optimized for wart therapyand the anatomic location of the warts (for example warts on the thickerskin of the hand might be formulated differently than that used forvaginal warts). An LED light source could be used for home use with 644nm in a battery powered unit wherein the topical formula was applieddaily and treatment of individual warts was performed with the properparameters until the warts disappeared.

For the situation of vaginal warts, a cylindrical device with an arrayof LED arranged and optically diffused such that the entire vaginalcavity could be properly illuminated in a medically performed procedurewould represent another embodiment of this therapy. A wide range ofsubstances can be utilized either as the primary chromophore or asadjunctive supporting therapy. These compounds are listed elsewhere inthis application. In another embodiment an immune stimulator is utilizedin conjunction with photomodulation with or without an exogenouschromophore. In yet another embodiment a higher powered light sourceeither narrow or broad band can be utilized with the same chromophoretherapy as outlined above, but with parameters selected so that theinteraction with the chromophore is non photomodulation, but ratherintense photothermal effect so as to damage or destroy the wart but withminimal damage to surrounding uninvolved and non supporting tissues.

In one embodiment a chlorophyll and carotenoid topical formulation isapplied and natural sunlight with or without a selective sunscreen areused to interact with the topical formulation. Another embodimentutilizes an injected or ultrasonically enhanced topical delivery of adye or photodynamic therapeutic dye or agent such as indocyanine greenwhich has been used for vascular injections safely in other medicalapplications.

Papulosquamous, eczematous and psoriasiform and related skin disorderscan be improved, controlled, reduced or even cleared by the samephotomodulation or photothermal interaction with endogenous or exogenouschromophores. The process outlined for warts and the other disorders inthis application may be used for such therapies. The use of ultrasoundis particularly useful in the more scaly disorders in this group ofdiseases as are enzyme peels and other methods with gently removescaling skin. Penetration of light into psoriasis presents for example amajor problem with current therapies. Penetration of drugs and topicalagents is likewise a major therapeutic challenge. If the dry skin on topof psoriasis is removed it is well known that this stimulates furthergrowth of the plaque or lesion of psoriasis—yet removal is needed toallow the drugs to penetrate and for light to penetrate. Currentlyalmost all psoriasis light therapy is ultraviolet light and thus therisk of skin cancer and also of photoaging is very significant with alifetime of repeated ultraviolet light therapy. Also such therapytypically involves treating large areas or even the entire body(standing in a large light therapy unit is like being in a tanning bedwhich is standing upright). Thus not only does the skin with psoriasislesions get treated, but also all the normal uninvolved skin typicallygets exposed to the damaging ultraviolet light.

Furthermore typical psoriasis treatments involve the use of oral drugscalled psoralens. These drugs cross link: DNA and are light activated.Thus DNA damage in produced not only by the ultraviolet light itself(like being out in sunlight but primarily ultraviolet A light), but inaddition the psoralen drug produced DNA damage. Safety in children in anobvious concern as is use in pregnant or childbearing women.

The use of a topical light activated exogenous chromophore such as mostof the agents listed in this application present no risk of DNA damageand also are generally very safe products—many are natural such aschlorophyll and can be safely used in children and pregnancy and childbearing age women. In addition the treatment is only activated where thetopical agent is applied—unlike the use of oral psoralen drugs thatactivate not only the entire skin but also the retina and other tissues.The light used for this therapy is not only low in power, but it is forthe most part visible or infrared light and is not ultraviolet—producingno DNA damage.

Thus the use of photo modulation or photothermal activation of exogenouslight activated chromophores such as described herein represents asignificant advance in safety and efficacy.

The photolyase embodiments described above also have some applicationfor diseases such as psoriasis. For some cases of psoriasis are veryextensive covering large amounts of the surface area of the body and maybe resistant to other known therapies. The application of a topicalformulation to the areas not being treated—or to all the body areasexposed to the traditional psoriasis phototherapy could receive a posttreatment with the photolyase and blue light therapy—think of this as atype of ‘antidote’ to the ultraviolet psoriasis phototherapy wherein therepair of DNA damage to normal tissue was facilitated immediatelyfollowing the psoriasis therapy—thus reducing significantly the risk ofskin cancer and photoaging in future years.

Another embodiment involves the use of such a photolyase preparation inthe evening after returning from a long day of occupational sun exposureor after an accidental sunburn. A spray or lotion containing thephotolyase could be applied and then photorepair/photareacitvation ofthe acutely damaged DNA in the skin could be performed—and this could beperformed with a large beam diameter home therapy unit—of by a whitelight source which contained enough of the desired wavelength or throughselective filtering at the proper parameters to produce this reaction.Additionally an antioxidant skin formulation could be also applied tominimize arrhythmia and other undesired effects of the sunburn. One suchembodiment would be the preparation described earlier with a combinationof vitamin C, vitamin E and glutathione and free fatty acids and one ormore keto acids. A similar formulation could contain these agents bututilize only one or two of the three antioxidants listed.

In vitro fertilization processes can also be enhanced byphotomodulation—with or without an exogenous chromophore. This cansimply target the cells or subcellular components themselves, asdescribed in the applicants copending U.S. patent application Ser. No.09/894,899 entitled “Method and Apparatus for Photomodulation of LivingCells”, which is hereby incorporated by reference in its entirety.

This can result in a greater success rate of fertilization and/or growthof embryos or other desirable effects on this process. In one embodimentan LED light source is used to treat sperm of animals or humans orgenetically engineered embryos or subcomponents thereof to enhancefertilization. Hair structure cells grown in cell tissue culture can bephotomodulated to multiply, differentiate (including turning stern cellsinto hair structure cells) or mature and develop prior to transplantinginto the host skin. Such photomodulation can be continued aftertransplantation to enhance the survival of transplants as well as toenhance the growth rate and hair quality of such transplants.

In another embodiment photolyase or other photoreparative or lightactivated DNA repair proteins or substances combined withphotomodulation can be utilized to ‘correct’ DNA damage in embryonictissues thus generating a normal or more normal embryo. This can beperformed in vitro or in utero (utilizing tiny fiber optic delivery ofthe proper light parameters—or the light can be delivered from outsidethe body into the womb without the risk of introducing a fiber opticdevice.

Another process in which photomodulation can be utilized for significantbenefit is in the stimulation of proliferation, growth, differentiation,etc of stem cells from any living organism. Stem cells growth anddifferentiation into tissues or organs or structures or cell culturesfor infusion, implantation, etc (and their subsequent growth after suchtransfer) can be facilitated or enhanced or controlled or inhibited. Theorigin of such stem cells can be from any living tissue or organism. Inhumans stem cells for these embodiments may come from any source in thehuman body, but typically originate from the bone marrow, blood, embryo,placenta, fetus, umbilical cord or cord blood, and can be eithernaturally or artificially created either in vivo, ex vivo or in vitrowith or without genetic alteration or manipulation or engineering. Suchtissue can come from any living source of any origin.

Stem cells can be photoactivated or photoinhibited by photomodulation.There is little or no temperature rise with this process althoughtransient local nondestructive intracellular thermal changes maycontribute via such effects as membrane changes or structuredconformational changes.

The wavelength or bandwidth of wavelengths is one of the criticalfactors in selective photomodulation. Pulsed or continuous exposure,duration and frequency of pulses (and dark ‘off period) and energy arealso factors as well as the presence, absence or deficiency of any orall co factors, enzymes, catalysts, or other building blocks of theprocess being photomodulated.

Photomodulation can control or direct the path or pathways ofdifferentiation of stem cells, their proliferation and growth, theirmotility and ultimately what they produce or secrete and the specificactivation or inhibition of such production.

Photomodulation can up-regulate or down-regulate a gene or group ofgenes, activate or inactivate enzymes, modulate DNA activity, and othercell regulatory functions.

Our analogy for photomodulation of stem cells is that a specific set ofparameters can activate or inhibit differentiation or proliferation orother activities of a stem cell. Much as a burglar alarm keypad has aunique ‘code’ to arm (activate) or disarm (inhibit or inactivate)sending an alarm signal which then sets in motion a series of events soit is with photomodulation of stem cells.

Different parameters with the same wavelength may have very diverse andeven opposite effects. When different parameters of photomodulation areperformed simultaneously different effects may be produced (like playinga simple key versus a chord on a piano). When different parameters areused serially or sequentially the effects are also different—in factdepending on the time interval we may cancel out the priorphotomodulation message (like canceling burglar alarm).

The selection of wavelength photomodulation is critical as is thebandwidth selected as there may be a very narrow bandwidth for someapplications—in essence these are biologically active spectralintervals. Generally the photomodulation will target flavins,cytochromes, iron-sulfur complexes, quinines, heme, enzymes, and othertransition metal ligand bond structures though not limited to these.

These act much like chlorophyll and other pigments in photosynthesis as‘antennae’ for photo acceptor molecules. These photo acceptor sitesreceive photons from electromagnetic sources such as these described inthis application, but also including radio frequency, microwaves,electrical stimulation, magnetic fields, and also may be affected by thestate of polarization of light. Combinations of electromagneticradiation sources may also be used.

The photon energy being received by the photo acceptor molecules fromeven low intensity light therapy (LILT) is sufficient to affect thechemical bonds thus ‘energizing’ the photo acceptor molecules which inturn transfers and may also amplify this energy signal. An ‘electronshuttle’ transports this to ultimately produce ATP (or inhibit) themitochondria thus energizing the cell (for proliferation or secretoryactivities for example). This can be broad or very specific in thecellular response produced. The health of the cells and theirenvironment can greatly affect the response to the photo modulation.Examples include hypoxia, excess or lack or ration of proper cofactorsor growth factors, drug exposure (e.g. reduced ubiquinone from certainanticholesterol drugs) or antioxidant status, diseases, etc. This isanother circumstance wherein oral or systemic replacement of such agentsor factors may be used to enhance the photomodulation effects. It shouldbe also noted that any process which causes the accumulation of suchagents—or conversely accelerates the inactivation or removal ofinhibitors of such agents would have as a net outcome the effect ofincreasing the concentration of these agents without directly addingsuch agents.

The as yet unknown mechanism, which establishes ‘priorities’ withinliving cells, can be photomodulated. This can include even thedifferentiation of early embryos or stem cell population. Exogenouslight activated chromophores may also be used alone or in combinationwith exogenous chromophores. Genetically altered or engineered stemcells or stem cells which have an inborn genetic error or defect oruncommon but desirable or beneficial trait may require a different‘combination’ of parameters than their analogous ‘normal’ stem cells ormay produce different cellular response if use the same combination ofparameters. Using various methods of photomodulation or other techniquesknown in the art more specific cellular effects may be produced by‘blocking’ some ‘channels’ that are photomodulated.

For example, consider an old fashioned juke box, if one selects theproper buttons one will set in motion a series of events resulting inthe playing of a very specific and unique record or song. If however onewere given a broom to push the buttons one would have to block all butthe desired button to be selective. Likewise pushing an immediatelyadjacent button will not produce the desired outcome.

The magnitude of effects on cells may also be very dependent on thewavelength (when other parameters are the same). One such example is thecontrast between irradiating chemical bonds in DNA with 302 nm lightversus 365 nm light—the 302 nm light produces approximately 5000 timesgreater DNA pyrimidine dimers than the 365 nm only a short distance upthe spectrum. Changing the wavelength can also convert the ratio or typeof these dimers. Thus seemingly subtle changes in photomodulation orphotochemical reaction parameters can produce very large and verysignificant differences in cellular effects—even at the subcellularlevel or with DNA or gene expression.

A final analogy is that photo modulation parameters can be much like a“morse code” to communicate specific ‘instructions’ to stem cells. Thishas enormous potential in practical terms such as guiding or directingthe type of cells, tissues or organs that stem cells develop ordifferentiate into as well as stimulating, enhancing or acceleratingtheir growth (or keeping them undifferentiated).

Another application of photomodulation is in the treatment of cellulite.Cellulite is a common condition which represents a certain outwardappearance of the skin in certain anatomic areas—most commonly on theupper legs and hips which is widely regarded as cosmeticallyundesirable. Cellulite is the result of a certain anatomic configurationof the skin and underlying soft tissues and fat which may involveabnormalities of circulation or microcirculation or metabolicabnormalities—predominantly in the fat and supporting tissues.Photomodulation or photothermal treatments of the adipocytes (fat cells)or their surrounding supporting structures and blood supply alone or incombination can reduce the appearance of cellulite and/or normalize thestructure and function of the tissues involved with the cellulite.

Photomodulation of adipocytes can be performed using endogenouschromophores such as the adipocytes themselves, their mitochondria orother targets within the adipocyte electron transport system orrespiratory chain or other subcellular components. Exogenous light orelectromagnetically activated chromophores can also be photomodulated(photoactivated or photo inhibited) or photothermal interactions canalso occur. Examples of such chromophores are listed elsewhere in thisapplication and can be topically or systemically introduced into thetarget tissues or adipocytes or surrounding blood vessels. The use ofexternally or internally applied ultrasound can be utilized either toenhance delivery of the chromophore or to alter local circulation or toprovide thermal effect or to provide destructive effect or anycombination of these actions.

In one embodiment the chromophore is delivered into the fat layer underthe skin on the thigh using external ultrasound to enhance skinpenneability and also enhance transport. The alteration of the stratumcorneum alone or in combination with the ultrasound can further enhancedelivery of the chromophore. External massage therapy from varioustechniques can be used to enhance the treatment process. In anotherembodiment chromophore is injected into the fat layer prior to treatmentwith light. Some light therapy with or without ultrasound may be used tophotomodulate or photothermally or ultrasonically increase or otherwisealter the circulation or microciruc1ation or local metabolic processesin the areas affected by cellulite or other tissues. The proper lightparameters are selected for the target adipocytes, blood vessels,exogenous chromophores, etc. Since some of the target tissues incellulite are deeper than for example wrinkles or acne, typically longenough wavelengths of light must be utilized so that the lightpenetrated deeply enough to reach the target tissue.

Various topical or systemic agents can also be used to enhance thecellulite reduction treatments. Some of these include various cofactorsfor the metabolic or adipocyte interactions described and have beenpreviously described herein.

Some topical agents inhibit hair growth rather than stimulate hairgrowth. Hair growth inhibitors include inhibitors of ornithinedecarboxylase, inhibitors of vascular endothelial growth factor (VEGF),inhibitors of phospholipase A2, inhibitors of S-adenosylmethionine.Specific examples of these, but not limited to, include licorice,licochalone A, genestein, soy isoflavones, phtyoestrogens, vitamin D,soy milk, inhibitors of nuclear factor kappa B (NF-kB), b3-AR adipocytereceptor, leptin, imiquinoid, urushiol, other topical or systemicimmunomodulators, sulfhydryl compounds, free radical scavengers,antiandrogens, sulfones, heterocyclic esters and amides, and inhibitorsof the metabolism of such agents, derivatives, analogs, conjugates,natural or synthetic versions or genetically engineered or altered orimmunologic conjugates with these agents. Since VEGF molecules have arelatively large size, removal of some portion of the stratum corneum ishelpful in enhancing penetration of the molecule into the skin. Smallerfragments of the VEGF molecule or peptides thereof may also be verybeneficial in accordance with the present invention.

In a preferred embodiment, VEGF molecules, and fragments or peptidesthereof are used in conjunction with ornithine decarboxylase for hairgrowth stimulation. Further enhancing the uses of these topicalcompositions is ultrasound application to maximize transdermalpenetration. Finally, using low-intensity light therapy tophotostimulate the hair growth structure within the skin is mostpreferred to further enhance treatment using VEGF with ornithinedecarboxylase that has been permitted to penetrate into skin with theaid of ultrasound.

Additional compositions for enhancing hair stimulation alone, or incombination with low-intensity light therapy and the various meansdisclosed herein for enhancing penetration include: retinoids, retinol,minoxidil, finesteride, topical aldosterone antagonists, larreadivaricata, glutamine peptides, caffeine, phytoestrogens, tissueinhibitors of metalloproteinase (TIMP), antioxidants, grape seedextracts, green tea and derivates thereof, prevotella intermedia,lipopolysaccharides, nitric oxide generating agents, oxygen generatingagents, polymixin, procyanidin B2, procyanidin C1, algae, yeastextracts, copper peptides, octylbutryate, capsicum, ginseng,niacinamide, soy, soy isoflavones, licorice, and genestin.

Also the same topical agents, exogenous light activated chromophores andtreatments described for cellulite above also are hereby incorporatedinto methods for stimulating and/or inhibiting the growth of hair.Increasing the circulation or microcirculation of the hair bearing skinor skin structure may also be accomplished by simply producingvasodilation by any method known to those skilled in this art.

An alternative application of the present invention is to use lighthaving a wavelength in the range of about 410 nm to 420 nm, orthereabouts. The use of blue light, in particular the 410-420 nm rangecan powerfully affect anti aging, stimulate collagen, and also remove,reduce, or normalize melanin pigmentation. This wavelength of light mayalso reduce or remove extra blood vessels in the skin most preferred forthis type of application is the use of blue fluorescent light, althoughother light sources disclosed herein can be effective for suchtreatment. The benefit of fluorescent lights, of course, are that theyare very inexpensive and do not require FDA approval for use. Thetreatment regimen includes a 10-15 minute exposure to the light source(which is up to 10 J/cm² total dose for 15 minutes.) In an alternativeembodiment, circadian rhythm treatment can be conducted using a similartreatment.

Another application of the present invention is for tattoo removal. TheFDA has approved the use of very high-power lasers for this, butaccording to the present invention, long-pulsed lasers and other lightsources at lower power can be employed to reduce or eliminate theappearance of tattoo inks in the skin with only a few, very shorttreatment sessions. In one embodiment of the invention, a home-use LEDarray, for example, can be employed at low power to reduce thevisibility of tattoo inks. When used at a light intensity level of from1 μJ/cm² to 10 J/cm², a wavelength of 644 nm can produce significantreduction in the visibility of tattoo inks in treatment sessions lasting0.1 to 100 minutes, suing either a continuous wave or 1 to 100 msecpulses with 1 to 100 msec interpulse intervals, repeated 1-20 times over7-120 days.

Alternatively, long pulsed diode laser at 800-810 nm work with pulsedurations in the 100-1000 millisec range, at from about 2-90 watts usingan 8.0 mm beam diameter is useful in another embodiment of theinvention, and this is for every color except red ink. For red tattooinks, great success great success has been shown with pulses of 40 msecwith a 595 nm pulsed dye laser. In another embodiment of the invention,multiple light sources with different wavelengths, usually a red and ayellow or red and green combination, can be used to remove all colors ofink during shorter, easier to control treatment sessions.

The present invention is further illustrated by way of the followingexamples.

EXAMPLE 1 Hair Growth Stimulation

Three patients with male pattern baldness are tested for stimulation ofhair growth before and after receiving treatment in accordance with thenon-ablative method of the present invention. Hair counts are taken fromtheir scalp by utilizing subjective evaluations conducted by trainedmedical personnel. The LED treatment includes subjecting the target areaof the patient's skin to a LED light having a pulse width of 250 msecand a pulse spacing of 250 msec for 90 pulses. Eight treatments over 12weeks to the entire face with 590 nm multichromatic LED at an intensityranging from 1.05-2.05μ Watts. Having a bandwidth of +/−5-15 nm, the LEDtherefore produces light in the wavelength range of from 575 nm to 605nm. Further, the treatment maintains a skin temperature below thethreshold of thermal injury. The average improvement in hair counts isshown in Table 1.

TABLE 1 Hair Count Pre treatments Post treatments Percent 0% 65%Improvement

EXAMPLE 2 Hair Growth Stimulation-Pulsed Treatment

A team of blinded expert graders viewing before and after photos ofpatients subjected to the non-ablative LILT (“Low Intensity LightTherapy”) of the present invention score the global improvement of hairthickness. Hair counting is also performed.

Six men with male pattern baldness were tested for hair growthstimulation and thickening of hair appearance. The LED treatmentincludes subjecting the target area of the patient's skin to a LED lighthaving a pulse width of 10 msec and a pulse spacing of 100 msec for aperiod of 100 pulses. Eight treatments over 12 weeks to the entire facewith 590 nm multichromatic LED at an intensity ranging from 1.0-2.0μWatts. Having a bandwidth of +/−5-15 nm, the LED therefore produceslight in the wavelength range of from 575 nm to 605 nm. Further, thetreatment maintains a skin temperature below the threshold of thermalinjury. The average increase in the appearance of hair density is shownin Table 2.

TABLE 2 Averaged Value Increased Week/Value Hair Density 0 weeks 0% 4weeks 6% 8 weeks 22% 12 weeks  54%

EXAMPLE 3 Hair Growth Stimulation-Continuous Wave Treatment

One female with frontal hair loss is tested for hair growth stimulationin accordance with the procedures described in Example 2. Measurementsby expert graders are taken from her scalp before and after treatmentwith a single continuous wave pulse for a total of 200 seconds from a590 nm multichromatic LED at an intensity of 1.05-2.05μ Watts. Eighttreatments spaced evenly over 12 weeks are administered to the patient'sfrontal scalp and forehead.

TABLE 3 Averaged Value of Week/Value Reduction 0 weeks 0% 4 weeks 12% 8weeks 28% 12 weeks  43%

EXAMPLE 4 Non-Ablative Skin Therapy for Hair Growth Stimulation PulsedTreatment

Human skin is exposed to 180 pulses of a narrowband, multi chromatic 590nm LED at an energy output of 1.05 microwatts to 2.05 microwatts with apulse duration (the length of each pulse) of 20 milliseconds and aninterpulse interval (time between each pulse) of 100 milliseconds. Thetreatment is repeated 8 times for 12 weeks to the entire faces of agroup of 6 men with severe pattern hair loss. The amount of hair growthas measured by a team of blinded expert graders viewing before and afterphotos of the treated skin and making hair counts is shown in Table 4.

TABLE 4 Treatment Time (weeks) Avg. % Increase in Hair Counts 0 0 4 8 824 12 68

EXAMPLES 5 Non-Ablative Skin Therapy for Hair Growth StimulationContinuous Wave Treatment

Human skin is exposed to 200 second continuous wave of a narrowband,multichromatic 590 nm LED at an energy output of 1.0 microwatts to 2.0microwatts. The treatment is repeated 8 times for 12 weeks to the entirescalp of a single male pattern baldness subject. The amount of hairgrowth as measured by a team of blinded expert graders viewing beforeand after photos of the treated skin is shown in Table 5.

TABLE 5 Treatment Time (weeks) % Hair Growth Stimulation 0 0 4 6 8 36 1272

EXAMPLE 6 Non-Ablative Skin Therapy for Hair Growth Stimulation PulsedLaser Diode

Also suitable for use in accordance with the present invention is alaser diode. Typical pulse durations will be from about 100 millisecondsto about 1 second, for pulsed treatment, and from about 1 second toabout 30 minutes for continuous wave treatment. Suitable operating powerfor the laser diode includes the range of from about 10 milliwatts toabout 1 watt with about 200 milliwatts to 800 milliwatts beingpreferred. Commercially available laser diodes having a wavelengthbetween 400 nm and 1000 nm can be used. For this example, human scalpskin is exposed to 90 pulses from an 810 nm laser diode at an energyoutput of 2.0 microwatts. An interpulse spacing of 100 milliseconds isused. The treatment is repeated 6 times for 12 weeks to the entire scalpof three males with scalp baldness. The amount of hair growth is shownin Table 6.

TABLE 6 Treatment Time (weeks) % Reduction (checks measured) 0 0 4 13 838 12 51

EXAMPLE 7 Hair Growth Stimulations-Pulsed Treatment

A team of blinded expert graders viewing before and after photos of 20patients subjected to the non-ablative LILT (“Low Intensity LightTherapy”) of the present invention score the global improvement ofreceding frontal hairlines at the temples.

Eight males and one female are tested for hair growth stimulation. Thelaser diode treatment includes subjecting the target area of thepatient's skin to a laser diode light having a pulse width of 400 msecusing a 10 cm beam diameter and a pulse frequency of 1 hz (1 pulse persecond). Three pulses are administered. Three treatments over 12 weeksto the frontal scalp and forehead with 810 nm lazer diode at anintensity ranging 200 milliwatts/cm² Thermal injury is produced withblood vessels included among the target chromophores (but no skin woundcare is needed). The average change in hair growth density is shown inTable 7.

TABLE 7 Averaged Value of Hair Week/Value Growth Increase 0 weeks 0% 4weeks 18% 8 weeks 31% 12 weeks  34%

EXAMPLE 8 Hair Growth Stimulation-Pulsed Treatment

A team of blinded expert graders viewing before and after photos ofpatients subjected to the non-ablative LILT (“Low Intensity LightTherapy”) of the present invention score the global improvement of haircounts.

Six males with severe scalp boldness are tested for hair growthstimulation. The laser diode treatment includes subjecting the targetarea of the patient's skin to a laser 20 diode light having a pulsewidth of 600 msec and a pulse frequency of 1 hz (1 pulse per second).Three pulses are administered. Six treatments over 12 weeks to theentire scalp with 940 nm laser diode with a 10 cm beam diameter at anintensity ranging 250 milliwatts/cm². Further, this treatment produces askin temperature sufficient to produce a non ablative thermal injury.The average hair count increase shown in Table 8.

TABLE 8 Averaged Increase in Hair Week/Value Counts 0 weeks 0% 2 weeks8% 7 weeks 31% 12 weeks  40%

EXAMPLE 9

Example 9 is carried out under identical conditions as Example 8, exceptthat a 940 nm diode laser with a power of 10 microwatt/cm² exposes thesubjects to twenty 50 millisecond pulses with an interpulse interval of250 milliseconds. Six treatments over 12 weeks are performed withsimilar results. Mechanism is non thermal photoactivation.

EXAMPLE 10

Example 16 is carried out under identical conditions as Example 9 exceptthat a 810 diode laser with a power of 2600 nanowatts/cm² and a beamdiameter of 10 cm exposes the subjects to 60,100 millisecond pulses withan interpulse interval of 100 milliseconds. Six treatments over 12 weeksare performed with similar results. The mechanism of action is nonthermal photoactivation.

EXAMPLE 11

Example 11 is carried out under identical conditions as Example 10,except with a 940 nm diode laser with a power of 2 m W/cm² exposes thesubjects to a continuous wave for 100 seconds. Four treatments over 12weeks are performed with similar results. Photoactivation non thermalmethod is used.

EXAMPLE 12

Example 12 is carried out under identical conditions as Example 11,except with a 595 nm flashlamp pulsed dye laser with a power of 2.5Joues/cm² exposes the subjects to 20 millisecond pulses, evenly spaced 4weeks apart. Four treatments over 16 weeks are performed with similarresults. Photothermal non ablative method.

EXAMPLE 13

Example 13 is carried out under identical conditions as Example 12, forthe purpose of hair growth regeneration. A 595 nm flashlamp pulsed dyelaser with a power of 6.0 Joues/cm² exposes the subjects to a single 40millisecond pulse, evenly spaced 4 weeks apart. Five treatments over 20weeks are performed. Hair density is increased by 42% and actual haircounts increased by 18%. Mechanism is thermal non ablative.

EXAMPLE 14

Example 14 is carried out under identical conditions as Example 13 forthe purpose of hair growth stimulation. A 532 Nd:YAG laser with a powerof 150 milliwatts/cm² and a beam diameter of 10 cm exposes the subjectsto a single minimally overlapped 30 millisecond pulse, evenly spaced 4weeks apart. Five treatments over 20 weeks are performed. Hair countsare increased by 28%. Method of thermal non ablative technique.

EXAMPLE 15

Example 21 is carried out under the same conditions on 5 male patternbaldness subjects for the purpose of hair growth stimulation. LED 590 nmat 50 msec pulses with 150 msec off time and 90 pulses. Eight treatmentsare performed at 1 week intervals and final assessment is made at 12weeks. In addition to hair growth stimulation similar to Example 10several other significant changes are noted including apparent‘restoration’ of color to previously gray hairs and also apparentthickening of hair shafts.

EXAMPLE 16

Example 16 is carried out under identical conditions for the purpose ofstimulating hair growth. Subjects have male pattern hair loss and are20-40 years of age with no scalp diseases. A 644 nm LED device with apower of 2.2 microwatts/cm² exposes the subjects to 200 msec pulses with200 msec off time between pulses for total of 50 pulses. Six treatmentsover 24 weeks are performed. Increase in appearance of hair growth is22%.

EXAMPLE 17

Example 17 is carried out on female subjects with alopecia areata formof patchy hair loss in the scalp. A 940 nm diode laser with a power of150 milliwatts/cm² and a 10 cm diameter beam exposes the skin in theaffected areas with continuous light for 4 minute exposures. Treatmentsare performed at 3 week intervals for 18 weeks. The alopecea areatalesions are reduced by 26% and spotty hair growth is observed inremaining bald patches.

EXAMPLE 18

Example 18 is carried out on acute hair loss from chemotherapy for thepurpose of stimulating hair regrowth. A 623 nm LED array exposes a 7inch by 10 inch rectangular area over the skin to 1.5 microwatts/cm² for60 pulses of 100 millisec on time and 100 msec off time. Treatments areperformed twice weekly until recovery of hair growth is accomplished.Recovery time is dependent on the severity of hair loss and reportedeyelining of chemotherapy as well as other undetermined factors.

EXAMPLE 19

A series of cell tissue cultures containing monolayers of complete humanhair follicles were treated in a comparison study to show the differencebetween treatment efficacy when conducted with a 595 nm pulsed dye laserand a 590 nm LED. The LED was at an energy intensity of 2microwatts/cm², pulsed for 50 ms with a 100 ms interpulse interval. Thenon-thermal photomodulation treatment using the LED used 50 pulses. The595 nm pulsed dye laser used a single pulse at an energy intensity of2.5 Joules/cm² and a pulse length of 0.5 milliseconds for photothermaltreatment. Analysis of hair shaft growth rate 5 days after treatment hadbeen administered showed no significant change for the controls. Thephotothermal dye laser treated hair follicles exhibited a 12% decreasein hair shaft growth rate relative to the controls. The hair folliclestreated with the non-photothermal photomodulation treatment of thepresent invention exhibited a 22% increase in hair shaft and growth raterelative to the controls.

1. A method for activating or inhibiting the differentiation of stemcells, comprising exposing the stem cells to a source of narrowbandmulti chromatic electromagnetic radiation under conditions effective toactivate or inhibit cell differentiation.
 2. The method of claim 1wherein the source of narrowband multi chromatic electromagneticradiation is at least one light emitting diode.
 3. The method of claim 1wherein the conditions effective to activate or inhibit celldifferentiation comprise continuous exposure to the source of narrowbandmultichromatic electromagnetic radiation.
 4. The method of claim 3wherein an energy fluence of no greater than 4 J/cm2 is delivered to thestem cells.
 5. The method of claim 1 wherein the conditions effective toactivate or inhibit cell differentiation comprise exposure to more thanone pulse of light from the source of narrowband multichromaticelectromagnetic radiation.
 6. The method of claim 3 wherein an energyfluence of no greater than 4 J/cm2 is delivered to the stem cells. 7.The method of claim 1 comprising applying a chromophore to the stemcells prior to exposure to the source of narrowband multichromaticelectromagnetic radiation.
 8. The method of claim 1 comprising applyingan exogenous chromophore to the stem cells prior to exposure to thesource of narrowband multi chromatic electromagnetic radiation.
 9. Themethod of claim 1 wherein the exposing comprises communicatinginstructions to the stem cells via the narrowband multichromaticelectromagnetic radiation as to the type of cells, tissues, or organsinto which the stem cells differentiate.